Bone is dynamic tissue that is remodeled constantly throughout life. Living bone tissue is replenished by the processes of resorption and deposition of bone matrix and minerals. This temporally and spatially coupled process, termed bone remodeling, is accomplished largely by two cell populations, the osteoclasts and osteoblasts. The remodeling process is initiated when osteoclasts are recruited from the bone marrow or the circulation to the bone surface. The matrix and minerals of the bone are subsequently replaced by osteoblasts recruited to the resorbed bone surface from the bone marrow. Resorption of bone is carried out mainly by osteoclasts, which are multinucleated cells that are formed by fusion of hematopoietic stem cells related to the mononuclear phagocyte series. Resorption of bone takes place in scalloped spaces where the osteoclasts are attached to components of the bone matrix. Osteoclasts have been linked to many diseases, including: marble disease, osteoporosis, fracture or trauma, bone metastasis, cancer, osteosarcoma, hypercalcemia and rheumatoid arthritis.
Increased osteoclast numbers and bone resorption are found in breast cancer metastasis (Hunt, et al. (2001) Br. J. Cancer (Scotland), 85(1):78–84).
Methods for identifying a compound useful for the treatment of bone disorders caused by osteoclast differentiation are described in EP 1087230.
Osteoclast differentiation inhibitors, such as notch ligand polypeptides, useful to treat bone disorders are disclosed in JP2001122798. TGF-beta has also been shown to stimulate proliferation and matrix synthesis of osteoblastic cells (Centrella, et al. (1987) J. Biol. Chem. 262:2869–2874), to inhibit the formation and activity of osteoclastic cells (Chenu, et al. (1988) Proc. Natl. Acad. Sci. U.S.A. 85:683–5687; Kiebzak, et al. (1988) J. Bone Min. Res. 3:439–446), and to stimulate local bone formation in vivo (Joyce, et al. (1990) J. Cell. Biol. 110:2195–2207; Noda and Camilliere (1989) Endocrinology 124:2991–2294). Other factors reported to stimulate bone growth include bone morphogenetic proteins (WO 88/00205), insulin-like growth factor (IGF) (Isgaard, et al. (1986) Am. J. Physiol. 250:E367–72), and parathyroid hormone (Slovik, et al. (1986) J. Bone & Min. Res. 1:377–381).
Methods for diagnosing skeletal disorders such as osteoporosis and osteoarthritis using a specific marker comprising IL-1 alpha, IL-1 beta, IL-6 and its receptor are described in WO 00/13024.
Osteoclast-specific genes and proteins have now been identified that are useful in detecting and isolating osteoclasts and identifying and producing agents which modulate osteoclast function.